Project description:- Background: Optimized diets during the first period of life may be most effective for improving gut and overall health. Here, we set up an interdisciplinary research pipeline to evaluate gut health benefits of early life nutrition ingredients through advanced integration of in vitro and modeling technologies that represent the infant gut environment. - Methods: In our InTESTine platform (TM), biopts of piglet gut tissue (Jejunum or Colon) were exposed (0-6h) to various infant/piglet-formula-milk based food matrices (-/+ prebiotics; -/+ predigestion by infant/piglet fecal microbiome). RNA expression of the piglet gut tissue biopts was measured by RNAseq. - Results: To be published in various papers. - Conclusion: To be published in various papers.
Project description:Infants and young children are more susceptible to common respiratory pathogens compared to adults, but can fare better against novel pathogens like SARS-CoV-2. The mechanisms by which infants and young children mount effective responses to respiratory pathogens are unknown. Here, we demonstrate through study of lungs and lung-associated lymph nodes (LLN) from infant and pediatric organ donors, aged 0-13 years, that bronchus-associated lymphoid tissue (BALT), develops in lungs during the first year of life. BALT structures, consisting of B cell follicles and T cell zones, increase in numbers in the early years, and subsequently decrease over childhood coincident with accumulation of memory T cells in the lung. Early life BALT contains germinal centers and supports B cell differentiation, clonal expansion, somatic hypermutation, and immunoglobulin class switching. High dimensional flow cytometry reveals seeding of lungs by newly formed B cells (transitional cells) during infancy coincident with the timing of maximal BALT formation. We further demonstrate increased lung-localized B cell responses during respiratory virus infection in infants. Together, our findings provide novel evidence for BALT as an early life adaptation for mobilizing in situ immune protection to the diverse respiratory challenges during this formative life stage.
Project description:Introduction: Thymic Stromal Lymphopoietin (TSLP) is a primarily epithelial-derived cytokine that drives type 2 allergic immune responses. Early life viral respiratory infections elicit high TSLP production, which leads to the development of type 2 inflammation and airway hyperreactivity. The goal of this study was to examine in vivo and in vitro the human airway epithelial responses leading to high TSLP production during viral respiratory infections in early infancy. Methods: A total of 129 infants (<1m – 24m, median age 10m) with severe viral respiratory infections were enrolled for in vivo (n=113), and in vitro studies (n=16). Infants were classified as “high TSLP” or “low TSLP” for values above or below the 50th percentile. High vs. low TSLP groups were compared in terms of type I-III IFN responses and production of chemokines promoting antiviral (CXCL10), neutrophilic (CXCL1, CXCL5, CXCL8), and type 2 responses (CCL11, CCL17, CCL22). Human infant airway epithelial cell (AEC) cultures were used to define the transcriptomic (RNAseq) profile leading to high vs. low TSLP responses in vitro. Results: Infants in the high TSLP group had greater in vivo type III IFN airway production (median type III IFN in high TSLP 183.2 pg/ml vs. 63.4 pg/ml in low TSLP group, p= 0.007) and increased in vitro type I-III IFN AEC responses after stimulation with a viral mimic (poly I:C). Our RNAseq data showed that infants in the high TSLP group had significant baseline upregulation of IFN signature genes (e.g., IFIT2, IFI6, MX1) and pro-inflammatory chemokine genes prior to viral mimic stimulation. Infants in the high TSLP group also showed a baseline AEC pro-inflammatory state characterized by increased production of all the chemokines assayed (e.g., CXCL10, CXCL8) in the absence of viral stimuli. Conclusion: High TSLP responses in the human infant airways are associated with pre-activated airway epithelial IFN antiviral immunity and increased baseline AEC production of pro-inflammatory chemokines. These findings present a new paradigm underlying the high production of TSLP in the human infant airway epithelium and shed light on the pathogenesis of viral respiratory illnesses during early infancy and beyond childhood.
Project description:Diet-microbe interactions play a crucial role in infant development and modulation of the early-life microbiota. The genus Bifidobacterium dominates the breast-fed infant gut, with strains of B. longum subsp. longum (B. longum) and B. longum subsp. infantis (B. infantis) particularly prevalent within the early-life microbiota. Although, transition from milk to a more diversified diet later in infancy initiates a shift to a more complex microbiome, with concurrent reductions in Bifidobacterium abundance, specific strains of B. longum may persist in individual hosts for prolonged periods of time. Here, we sought to investigate the adaptation of B. longum to the changing infant diet during the early-life developmental window. Genomic characterisation of 75 strains isolated from nine either exclusively breast- or formula-fed infants in the first 18 months of their lives revealed subspecies- and strain-specific intra-individual genomic diversity with respect to glycosyl hydrolase families and enzymes, which corresponded to different dietary stages. Complementary phenotypic growth studies indicated strain-specific differences in human milk oligosaccharide and plant carbohydrate utilisation profiles between and within individual infants, while proteomic profiling identified proteins involved in metabolism of selected carbohydrates. Our results indicate a strong link between infant diet and B. longum subspecies/strain genomic and carbohydrate utilisation diversity, which aligns with a changing nutritional environment i.e. moving from breast milk to a solid food diet. These data provide additional insights into possible mechanisms responsible for the competitive advantage of this bifidobacterial species and their long-term persistence in a single host and may contribute to rational development of new dietary therapies for this important development window.
Project description:Prenatal exposures such as infections and immunisation may influence infant responses. We had an opportunity to undertake an analysis of responses in infants within the context of a study investigating the effects of maternal mycobacterial exposures and infection on bacille Calmette-Guerin (BCG) vaccine-induced responses in Ugandan infants. Gene expression profiles for pathways associated with maternal LTBI and with maternal BCG scar were examined using samples collected at one (n=42) and six (n=51) weeks after BCG immunisation using microarray. Interferon and inflammation response pathways were up-regulated in infants of mothers with LTBI at six weeks, and in infants of mothers with a BCG scar at one and six weeks after BCG immunisation. Maternal BCG scar had a stronger association with infant responses than maternal LTBI, with an increased proinflammatory immune profile.
Project description:Microbiota assembly in the infant gut is influenced by time and duration of dietary exposure to breast-milk, infant formula and solid foods. In this randomized controlled intervention study, longitudinal sampling of infant stools (n=998) showed similar development of fecal bacterial communities between formula- and breast-fed infants during the first year of life (N=210). Infant formula supplemented with galacto-oligosaccharides (GOS) was most efficient to sustain high levels of bifidobacteria compared to formula containing B. longum and B. breve or placebo. Metabolite (untargeted) and bacterial profiling (16S rRNA/shallow metagenomics sequencing) revealed 24-hour oscillations and integrated data analysis identified circadian networks. Rhythmicity in bacterial diversity, specific taxa and functional pathways increased with age and was most pronounced following breast-feeding and GOS-supplementation. Circadian rhythms in dominant taxa were discovered ex-vivo in a chemostat model. Hence microbiota rhythmicity develops early in life, likely due to bacterial intrinsic clock mechanism and is affected by diet.